(en)Adsorptive, protein-binding aluminum oxyhydroxides are prepared by mixing carbonate-free, highly hydrated, aluminum oxyhydroxide containing aqueous suspensions with water soluble additives that furnish coordinating moieties with the aluminum compound and drying the resultant mixture. The protein-binding aluminum oxyhydroxides can be made resuspendable by acidifying to a pH value of between about 4 and about 6.5. Such acidification can occur either before or after drying.

1.ApplicationNumber: US-58633390-A
1.PublishNumber: US-5558858-A
2.Date Publish: 19960924
3.Inventor: RUBINO; ANDREW M.
SICILIANO; ARTHUR A.

4.Inventor Harmonized: RUBINO ANDREW M(US)
SICILIANO ARTHUR A(US)

5.Country: US
6.Claims:
(en)Adsorptive, protein-binding aluminum oxyhydroxides are prepared by mixing carbonate-free, highly hydrated, aluminum oxyhydroxide containing aqueous suspensions with water soluble additives that furnish coordinating moieties with the aluminum compound and drying the resultant mixture. The protein-binding aluminum oxyhydroxides can be made resuspendable by acidifying to a pH value of between about 4 and about 6.5. Such acidification can occur either before or after drying.

7.Description:
(en)CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation of our application Ser. No. 289,687, filed Aug. 3, 1981, now abandoned.


BACKGROUND OF THE INVENTION
This invention relates to the co-drying of highly hydrated, relatively inert, carbonate-free aluminum oxyhydroxide suspensions. The suspensions are useful as adsorptive, protein-binding agents. Furthermore, one aspect of this invention relates to resuspendable, adsorptive, protein-binding agents. This invention also concerns topical skin compositions utilizing the agents produced in accordance with this invention.
It is well known to those skilled in the art that aluminum hydroxide gels are irreversibly degraded upon drying. The dehydration processing effectuates the loss of "water-of-constitution", among other entities, resulting in the destruction of most of the positive attributes characteristic of such gels, which properties serve as the very basis of their use in many applications. Illustrative degradative changes which can result are the following:
(1) alteration of the physiochemical structure of the products affecting their surfaces as well as their chemical reactivities;
(2) loss of adsorbent capacity;
(3) impairment of suspendability;
(4) increased density;
(5) increased particle size; and
(6) reduced viscosity.
The degradation of aluminum hydroxide gels upon dilution with water is discussed in "A Vehicle For Stabilizing Aluminum Hydroxide Gel" by Kerkhof, N. J.; Hem, S. L. and White, J. L., JOURNAL OF PHARMACEUTICAL SCIENCES, 75, Vol. 64, No. 12, pp. 2030-2032, Dec. 1975.
U.S. Pat. Nos. 4,112,072 and 4,115,553 are directed to producing dried antacids. These patents describe the codrying of certain basic reactive aluminum bicarbonate-carbonate compounds with polyols to form novel antacid tablets.
U.S. Pat. No. 3,599,150 concerns a freeze stable suspension of an aluminum hydroxide gel. The suspension has an alum-precipitated aqueous extract or aqueous pyridine extract of an antibody producing antigenic substance absorbed thereon in an aqueous solution containing a water-soluble non-toxic polyhydric alcohol and water-soluble non-toxic polymers. This patent, however, is not concerned with co-drying of the aluminum hydroxide gel.
Non-reactive aluminum oxyhydroxides in the wet state, i.e., suspended in water, are known as good adsorbers. For example, such suspensions are used in vaccines as toxin adsorbers (an adsorbent is a material that attracts and holds to its surface a gas, liquid, or solid ). Heretofore, these gels were useful only in the wet state. It was recognized that it was uneconomical to "ship large quantities of water around" with the aluminum hydroxide and that it would be advantageous to concentrate the aluminum hydroxide and resuspend it when needed. Attempts to dry such suspensions in order to concentrate them have heretofore not met with success due to the degradation upon drying of aluminum hydroxide as discussed above.
Heretofore, there has been no teaching of co-drying an inactive aluminum oxyhydroxide gel to produce an adsorptive, protein-binding agent. Furthermore, no such agent has heretofore been produced with sufficient resuspendability properties.
SUMMARY OF THE INVENTION
There has now been discovered a method to produce adsorptive, protein-binding aluminum oxyhydroxides. Further, there has now been discovered a method to produce absorptive, protein-binding, resuspendable aluminum oxyhydroxides.
A carbonate-free highly hydrated, aluminum oxyhydroxide containing aqueous suspension which is relatively inert towards alkalis and acids is mixed with a water soluble additive. The additive furnishes coordinating moieties with aluminum. The resulting mixture is then dried to form solid particles.
A resuspendable, protein-binding, absorptive aluminum oxyhydroxide is prepared by acidifying the aluminum oxyhydroxide-additive mixture. Such acidification can be conducted either when the aluminum oxyhydroxide is in aqueous suspension, or after the mixture has been dried. If acidified after drying, the solid particles are mixed with water prior to the introduction of acid. In all cases, acidification is conducted to yield a pH value of between about 4 and about 6.5.


BRIEF DESCRIPTION OF THE DRAWING
The FIGURE is a plot of protein binding capacity vs. glycerine for co-dried Al 2 O 3 -glycerine powders.


DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to co-drying carbonate-free, highly hydrated, aluminum oxyhydroxide suspensions which are relatively inert towards weak alkalis and acids in such a manner as to minimize or totally avoid degradation of the suspensions. The aluminum oxyhydroxide compounds that can be utilized in this invention include any inert aluminum hydroxide in which only the aluminum and the hydroxy and/or oxy entities are present, such as, for example, boehmite (alpha alumina monohydrate) and diaspore (beta alumina monohydrate). These compounds are distinguished from "reactive-grade aluminum hydroxide" which contain carbonate/bicarbonate. Such reactive compounds which find wide use as antacids, inter alia, are distinguished from inert aluminum hydroxide by simple carbon dioxide evolution analysis.
The additive mixed with the aluminum oxyhydroxide must be capable of furnishing coordinating moieties with aluminum and also must be soluble in water. If the product of the co-drying method of the present invention is to be utilized as an agent in a skin composition, the additive must further be topically acceptable, i.e., safe for use on the skin.
The additive can be an alcohol, sugar, amino acid, polysaccharide or polyfunctional nitrogen containing compound.
Non-limiting examples of suitable alcohols, i.e. polyhydric compounds, for use in the present invention as additives include glycerol, sorbitol, mannitol, polyethylene glycol (Carbowax), polypropylene glycol, butylene glycol and xylitol.
Non-limiting examples of suitable sugars that can be used as additives in the present invention include lactose, sucrose and glucose.
Non-limiting examples of suitable polyfunctional nitrogen containing compounds that may be used as additives in this invention include amino acids, such as L-glutamic acid; urea; glycine and beta-alanine. Use of amino acids of suitable strengths, i.e. concentrations, would allow the use of such acids to serve the dual function as an additive and acidifier when a resuspendable product is desired.
Non-limiting examples of polysaccharides that may be utilized as additives in the present invention include corn starch, "VEEGUM", "CERULOSE", "CARBOPOLS" and "CELLOSIZE".
The weight ratio of aluminum oxyhydroxide, calculated as aluminum oxide to additive present in the suspension prior to drying, ranges between about 10:1 and about 3:2, more particularly between about 6:1 and about 3:2. Based on the product, after drying, the additive can amount to between about 5 weight percent and about 30 weight percent of total product. The point of determination for the amount of additive, either before or after drying, is not per se critical and only has significance when volatile additives are utilized. A volatile additive will dissipate to some degree during drying depending on its volatility and the drying temperature. The weight ratios of additive to aluminum oxide as given above assume no loss of additive during drying. It would be a simple matter for one practicing this invention to calculate the estimated loss of additive due to evaporation and then add extra additive in anticipation of such loss. For a non-volatile additive such as corn starch, the foregoing procedure would be unnecessary.
The mixture of additive and aluminum oxyhydroxide compound is subjected to co-drying at appropriate temperatures. High drying temperatures, however, should not be utilized since there is a tendency to break bonds at high temperatures. It is advantageous to drive-off as much moisture as possible without over-drying the mixture. It is preferred to dry the mixture to attain between about 55 weight percent and about 65 weight percent aluminum oxyhydroxide, as calculated as aluminum oxide.
Any convenient drying method can be employed, such as, for example, spray drying, vacuum drying and hot air circulating ovens. The type of drying utilized will generally determine the particle size of the resultant solids. It is preferred in many instances to form a fine powder. Such powder can, for example, be produced using spray drying techniques or other drying techinques producing larger particles which are subsequently-comminuted via various grinding techniques known in the art.
Although it is usually desired to minimize the amount of additive, such amount is directly proportional to protein-binding capacity. Protein binding is enhanced by increasing the surface area of the aluminum containing compound particles, i.e., fine particle size. The suspendability of the dried products of this invention are inversely proportional to the pH of their respective suspensions.
The more concentrated the product, the less expensive the shipping costs due to elimination of unnecessary water being carried along with the useful product. Thus it is advantageous to use a product that is readily resuspendable with water.
To obtain a protein-binding, adsorptive agent that is resuspendable, acid must be utilized. Acidification can be conducted either prior to co-drying or after codrying. It is preferred to acidify prior to co-drying in order to produce a concentrated resuspendable solution. In such case, the aluminum oxyhydroxide in aqueous suspension is acidified to yield a pH value for the suspension of between about 4 and about 6.5, more particularly between about 5 and about 6. The acidified suspension is then mixed with the additive and co-dried to the desired degree. Alternatively, the aluminum oxyhydroxide aqueous suspension can be mixed with additive and then acidified to the pH range as given above prior to co-drying. The acidification can be conducted with any moderately strong acid such as, for example, hydrochloric acid, nitric acid and sulfuric acid, just to name a few. Acidification can also be carried out with compounds which yield acids upon hydrolysis such as AlCl 3 .
Moreover, acidification can be conducted after co-drying. In such case, the co-dried product is mixed with water, preferably to form a suspension and acidified to the pH range as given above.
The adsorptive, protein-binding aluminum oxyhydroxide agent produced by the method of the present invention can be employed in topical skin compositions. It can be used alone or in combination with other ingredients to form useful compositions for such products as sun screens, wrinkle fillers, acne medications, poison ivy remedies, burn remedies, anti-fungicides, antiseptics, analgesics, cosmetics, for example, lipsticks, makeup, and skin creams, just to name a few. Such other ingredients utilized in conjunction with the product of the present invention to form topical skin compositions include emulsifiers, such as the combination of glycerol monostearate, triethanolamine and stearic acids; thickeners such as stearic acid; emollients such as isopropyl myristate and humectants such as glycerine. Typical formulations are given as follows:

______________________________________Co-Dried Powder Produced In Accordance WithThe Present Invention - Approximate Analysiswt. % Al.sub.2 O.sub.3 60.10wt. % Glycerine 17.30wt. % Chloride 3.40wt. % Na 0.45wt. % SO.sub.4 0.71wt. % Water 19.04 (some water may exist as OH.sup.-)pH (4% Suspension) 5.1Bulk Density 0.77 g/ccProtein Binding Capacity 1.50 mg/mg Al.sub.2 O.sub.3 at pH 5.5OintmentAl.sub.2 O.sub.3 - Glycerine Powder as given above 3.2 wt. %Mineral Oil 15.0 wt. %Petrolatum 76.8 wt. %Polyoxethylene 4 Sorbitan Monostearate 5.0 wt. %("TWEEN 61")PowderAl.sub.2 O.sub.3 - Glycerine Powder as given above 3.2 wt. %Talc 93.8 wt. %Magnesium Stearate 3.0 wt. %______________________________________Creams wt. % wt. %______________________________________Al.sub.2 O.sub.3 - Glycerine Powder as given above 5.0 5.0"ARLACEL 165" (Glycerol Monostearate and 3.5 3.5Polyoxyethylene Stearate)Mineral Oil 5.0 3.0Isopropyl Myristate 3.0 6.0Propylene Glycol 2.0 1.0Cetyl Alcohol 1.5 4.0Methyl Paraben 0.2 0.2Propyl Paraben 0.05 0.05"MYRJ 52" (Polyoxyethylene 40 Stearate) -- 0.5Titanium Dioxide -- 0.2Deionized Water 79.75 76.55______________________________________

The present invention produces an aluminum oxyhydroxide agent having the following attributes:
(1) oil absorption (an absorbent is a material that "sucks up" or incorporates liquids, gases, etc.)
(2) thixotropic;
(3) protein-binding
(4) resistant to being washed away;
(5) esthetically pleasant;
(6) stable;
(7) non-tacky;
(8)
non-greasy;
(9) non-irritating;
(10) non-toxic;
(11) compatible with oxidizing agents, for example, hydroperoxide and benzoperoxide;
(12) having a broad pH range; and
(13) resuspendable (when acidified).
The invention is further described by reference to the following specific, non-limiting examples.
EXAMPLES 1-10
Effect of Glycerol Levels on Resuspendability of Co-Dried Products
Examples 1-5 (without HCl)
Five different Al 2 O 3 /glycerol weight ratio levels were utilized for examination of resuspendability: 3/0, 6/1, 3/1, 2/1, 1.5/1. To each batch of Al 2 O 3 , glycerol was added according to the formula: ##EQU1##
The source for Al 2 O 3 used throughout all the examples herein was Reheis Chemical Company "F-5000" gel. "F-5000" is a carbonate-free, highly hydrated, aluminum oxyhydroxide gel which is relatively inert towards weak alkalis and acids.
5500 grams of 9.6 wt.% Al 2 O 3 were added to an 18 liter Nalgene polypropylene vessel. Ten liters of well water were added to the gel and the mixture was homogenized with a Premier dispersator for two hours. From this slurry, five aliquots of 3000 grams each were taken, and each was placed in an 8 liter Nalgene polypropylene vessel.
Example 1
To the first aliquot was added 17.1 grams of glycerol according to the above formula. The slurry was agitated for an hour and screened through a #40 sieve before spray drying. Before the slurry was spray dried, two liters of well water were added to the slurry to improve pumpability. The slurry was spray dried at 120°-125° C. in a 3 foot circular Bowen spray dryer employing a two-fluid nozzle head. Air pressure was set at 80 psig and feed rate at 100 ml/min. This procedure yielded about 150 grams of finely divided, free-flowing, white powder with a pre-spray dry Al 2 O 3 to glycerol rate of 6/1 (see Table 1).
To demonstrate the resuspendability of the Al 2 O 3 -glycerol co-dried system with HCl, 2 grams of the above powder was added to 25 grams deionized water in a 4"×1" glass vial. With its cap in place, the vial was shaken ten times and three drops (approximately 0.14 grams) of 31% HCl was added to the vial by a medicine dropper. The vial was again shaken ten times. The vial approximated 4 wt % Al 2 O 3 (Example 1A). Resuspendability of an 8% system was also tested using 4 grams of powder and 5 drops (approximately 0.24 grams) of 31% HCl in 25 grams deionized water (Example 1B).
After standing overnight, the pH's of the vials were measured with a Beckman SS-3 pH meter standardized at pH 5 and pH 7.
Example 2
This example is identical to the above Example 1 with the exception that 34.1 grams of glycerol were added to the slurry for a projected 3/1 ratio of Al 2 O 3 to glycerol. Spray drying parameters and resuspendability techniques for 4% and 8% resuspensions were identical to Example 1 and for succeeding Examples 3-5.
Example 3
In this example 51.2 grams of glycerol was used to achieve a 2/1 ratio of Al 2 O 3 to glycerol.
Example 4
In this example 68.2 grams of glycerol was used with the resultant slurry having a 3/2 ratio of Al 2 O 3 to glycerol.
Example 5
No glycerol was used in this slurry which served as the 3/0 control.
The above spray dried slurries were analyzed for % Al 2 O 3 and reported in Table I herein.
Resuspendability of the Al 2 O 3 -glycerol co-dried systems with HCl added on resuspension is shown in Table II herein.
Examples 6-10 (with HCl)
5000 grams of 9.6 wt.% Al 2 O 3 were added to an 18 liter Nalgene polypropylene vessel. To this, three liters of well water were added. The pH of the slurry was then adjusted to 4.8 with 62 ml of 31% HCl under constant agitation with a Premier dispersator. The mixture was homogenized for two hours. From this slurry, five aliquots of 1800 grams each were taken and placed in an 8 liter Nalgene polypropylene vessel.
Example 6
To the first 1800 gram aliquot was added 18 grams of glycerol under constant agitation with the dispersator. The slurry was agitated one hour, and then screened through a #40 mesh sieve before spray drying (No extra well water was added to the slurry since it was pumpable). The spray drying parameters followed exactly those enumerated above in Example 1. 130 grams of finely divided, free-flowing powder resulted with a 6/1 pre-spray dry Al 2 O 3 to glycerol ratio (see Table II).
Resuspendability of this system was achieved by adding 2 grams of the powder to 25 grams deionized water in a 4"×1" glass vial. The vial was shaken ten times and left to stand overnight. After a minimum of 24 hours, pH's and descriptions were recorded.
Example 7
This example was identical to Example 6 except 36 grams of glycerol was added to the slurry to yield a 3/1 ratio. Dilution, spray drying parameters and resuspendability techniques for 4% resuspensions were identical to Example 6 for this and the succeeding Examples 8 through 10.
Example 8
The third aliquot received 54 grams of glycerol for an Al 2 O 3 /glycerol ratio of 2/1.
Example 9
72 grams of glycerol were added to the fourth 1800 gram portion for a 3/2 ratio Al 2 O 3 to glycerol.
Example 10
To the last aliquot of slurry, no glycerol was added.
The spray dried slurries in each of the above Examples 6-10 produced 130-140 grams of finely divided, free-flowing, white powder. Analyses of these powders is given in Table III herein.
Table IV given herein describes resuspendability of the Al 2 O 3 -glycerol-HCl system at various glycerol concentrations.
Examples 11-15
Effect of pH on Resuspendability
In the following examples, the effect of pH on Al 2 O 3 -glycerol-HCl co-dried systems is demonstrated. Varying amounts of HCl was used prior to spray drying to achieve powders of different pH values.
To 6000 grams of 9.6% Al 2 O 3 gel in an 18 liter Nalgene polypropylene vessel was added 3600 grams of well water and the resultant mixture was slurried with a Premier dispersator for two hours. This slurry was then split into five 1800 grams aliquots each and put into 8 liter Nalgene polypropylene vessels. Each of the five portions was acidified to a different extent as shown in Examples 11 through 15.
Example 11
To the first 1800 gram aliquot was added 36 grams glycerol and 15.7 ml 31% HCl under constant agitation from a dispersator. The pH was measured and found to be 4.3. 130 grams of finely divided, free-flowing, white powder resulted after spray drying at parameters mentioned in Example 1. Resuspension of this powder and the powders of Examples 12 through 15 were according to the procedures of Example 6.
Example 12
To this aliquot was added 36 grams of glycerol and 138 ml 31% HCl. After agitation, the pH was read as 4.8.
Example 13
36 grams of glycerol and 12.7 ml HCl were added to the third aliquot to give a final pH of 5.5. Also, one liter of well water was added to make the slurry pumpable.
Example 14
36 grams of glycerol, 8.3 ml 31% HCl and three liters of well water were added to this sample.
Example 15
36 grams of glycerol, 8.3 ml 31% HCl, three liters of well water, and no HCl were added to this sample before spray drying.
The results of the resuspendibility tests at different pH's are given in Table V herein.
Examples 16-20
Effect of Concentration on Resuspendability
Superior resuspendability of this invention over a wide range of concentrations are shown below using Al 2 O 3 -glycerol-HCl co-dried systems. Each of the examples outlined below (Examples 16 through 20) used powder synthesized in accordance with the procedures of Example 7. The results for Examples 16-20 are given in Table VI herein.
Example 16
One gram of Example 7 powder and 25 grams of deionized water were put into a 4"×1" glass vial and shaken ten times. This represented the 2% Al 2 O 3 example. Except for powder quantities, all resuspensions were performed identically and followed the procedures given in Example 6.
Example 17
This example is a duplicate of Example 7.
Example 18
Three grams of powder gave approximately a 6% Al 2 O 3 resuspension.
Example 19
Four grams of powder resulted in an 8% resuspension.
Example 20
Five grams of powder resuspended for a 10% Al 2 O 3 level.
Examples 21-33
Order of Component Addition in Relation To Spray Drying on Resuspendability
Resuspendability studies were performed on four different variations of co-dried powders: Al 2 O 3 alone, Al 2 O 3 co-dried with glycerol, Al 2 O 3 co-dried with glycerol and HCl, and Al 2 O 3 co-dried with HCl. To each of these powders glycerol, HCl, or both were added after spray drying. The resulting thirteen examples examined at 4% and 8% Al 2 O 3 .
5000 grams of 9.6 wt. % Al 2 O 3 were added to an 18 liter Nalgene polypropylene vessel. Nine liters of well water was added to the gel and the mixture was homogenized with a Premier dispersator for two hours. This batch was then split into two unequal sized aliquots; one, 7625 grams and the other, 6120 grams. The larger portion was acidified to pH 4.8 with 27 ml of 31% HCl in an 8 liter Nalgene polypropylene vessel. The smaller portion received no HCl.
The acidified batch was split into two equal portions of 3800 grams, each put into an 8 liter Nalgene polypropylene vessel. To one of these 3800 gram batches was added 43.4 grams of glycerol. This batch was agitated for one hour. The other 3800 gram batch received no glycerol.
The unacidified half was also split into two aliquots of about 3060 grams each. Again, each was placed in an 8 liter Nalgene polypropylene vessel, One portion received 35.0 gram glycerol according to the formula given for Examples 1-5, and one portion received no glycerol. The regime for Examples 21-33 is given in Table VII herein; the results for Examples 21-33 are given in Tables VIII and IX herein.
The slurries were all spray dried according to Example 1, but 2 liters of well water had to be added to the unacidified slurries to make them pumpable.
Examples 21-26
Spray Dried Al 2 O 3 Plus UnCo-Dried Adjuvants
Example 21A
To a 4"×1" glass vial containing 25 grams of deionized water was added two grams of Al 2 O 3 powder as prepared above. The vial was shaken ten times and then 4 drops of 31% HCl were added to the vial by a medicine dropper and shaken again for ten times. The vial was left overnight at which time a pH reading was taken and observations were made. This represented a 4% Al 2 O 3 sample. Examples 22 through 26 follow the above procedure with the stated changes.
Example 21B
An 8% Al 2 O 3 sample was also made up with 4 grams of powder in 25 grams of deionized water plus 5 drops HCl.
Example 22A
4% Al 2 O 3 and 3 drops HCl.
Example 22B
8% A1303 and 4 drops HCl.
Example 23A
4% Al 2 O 3 , 3 drops glycerol (0.2 grams), and 4 drops HCl. Amount of glycerol to each vial was figured according to formula given in Examples 1-5.
Example 23B 8% Al 2 O 3 , 6 drops glycerol (0.4grams), and 5 drops HCl.
Example 24A
4% Al 2 O 3 , 3 drops HCl, 3 drops glycerol.
Example 24B
8% Al 2 O 3 , 4 drops HCl, and 3 drops glycerol.
Example 25A
4% Al 2 O 3 and 6 drops glycerol.
Example 25B
8% Al 2 O 3 and 6 drops glycerol.
Example 26A
4% Al 2 O 3 ; no additives.
Example 26B
8% Al 2 O 3 ; no additives.
Examples 27-29
Al 2 O 3 -glycerol co-dried powder was used in Examples 27 to 29. These resuspensions were prepared according to the procedure in Example 21A.
Example 27A
4% Al 2 O 3 and 3 drops HCl.
Example 27B
8% Al 2 O 3 and 4 drops HCl.
Example 28A
4% Al 2 O 3 and 4 drops HCl.
Example 28B
8% Al 2 O 3 and 5 drops HCl.
Example 29A
4% Al 2 O 3 ; no additives.
Example 29B
8% Al 2 O 3 ; no additives.
Examples 30-31
Al 2 O 3 -Glycerol-HCl Co-Dried Systems--No Additives
Al 2 O 3 -Glycerol-HCl Co-Dried powder was used in Examples 30A and 30B. These resuspensions also followed the procedure given in Example 21A.
Example 30A
4% Al 2 O 3
Example 30B
8% Al 2 O 3
Example 31A
4% Al 2 O 3 using powder prepared according to Example 11.
Example 31B
8% Al 2 O 3 using powder prepared according to Example 11.
Examples 32-33
Al 2 O 3 -HCl Co-Dried Systems
Al 2 O 3 -HCl Co-Dried powder was used in Examples 32 and 33. These resuspensions followed the procedure given in Example 21A.
Example 32A
4% Al 2 O 3 and 3 drops glycerol.
Example 32B
8% Al 2 O 3 and 6 drops glycerol.
Example 33A
4% Al 2 O 3 ; no additives.
Example 33B
8% Al 2 O 3 ; no additives.
Examples 34-50
Resuspendability of Al 2 O 3 -Adjuvant Co-Dried Systems
Examples 34-50 show the superior resuspendability of Al 2 O 3 gel co-dried with a number of additives, thirteen of eighteen having a positive effect on resuspendability.
5500 grams of Al 2 O 3 gel and ten liters of well water were slurried with a dispersator in an 18 liter reaction vessel for two hours. Four 4000 gram aliquots were taken from this main batch and each was mixed in four 8-liter reaction vessels. This diluted the gel from 9.6% Al 2 O 3 to 3.4% Al 2 O 3 . All slurries possessed 3/1 Al 2 O 3 to additive ratios. Analyses for the powders used in Examples 34-50 are given in Table X herein. The results for Examples 34-50 are given in Tables XI and XII herein.
Example 34A
To one of the 4000 gram aliquots was added 45.5 grams of sucrose according to the formula given for Examples 1-5. The slurry was mixed in a dispersator for one hour. Two liters of additional well water were added to make the gel pumpable. The slurry was then spray dried and resuspended at 4% according to Example 1. The following Examples 35 to 50 follow the above example except that in Examples 38 through 50, 3000 grams of slurry and 34.1 grams of additive were used. The additives utilized were as follows:
sucrose--sucrose USP
lactose--Fisher ACS--lactose
sorbitol--ICI 70% sorbitol solution
polypropylene glycol
Carbowax 200--Union Carbide "CARBOWAX 200"; Grade 1, 2 propanediol
Carbowax 400--Union Carbide "CARBOWAX 400"
Carbowax 600--Union Carbide "CARBOWAX 600"
stearic acid--Baker certified stearic acid
citric acid--Pfizer citric acid USP
potassium citrate--Fisher certified potassium citrate
corn starch--Sargent-Welsh corn starch
Gelatin--Atlantic Gelatin edible 200B
glycine--Walker glycine USP
beta-alanine--Fisher beta-alanine purified grade
L-Glutamic acid--Fisher certified glutamic acid
Veegum--"VEEGUM" regular grade--R.T. Vanderbilt Inc.
Urea--Fisher ACS grade
PVP K-30--General Aniline & Film Corp. PVP (polyvinylpyrolidine) K-30 USP
PVP K-60--General Aniline & Film Corp. PVP (polyvinylpyrolidine)
Examples 51-71
Protein Binding
A known excess of protein standard was mixed with the sample. The non-adsorbed protein was spectrometrically determined and subtracted from the total added protein.
Protein Reagent
A protein reagent was prepared by pipetting 30 ml of deionized water into a 100 ml breaker. 1.596 grams of bovine albumin Fraction V powder, Armour Pharmaceutical Company, was added to the water. The resultant mixture was gently stirred to effect solution. The solution was then filtered through Whatman #4 filter paper and stored in a glass stoppered flask.
Preparation of Standard Curve
Protein reagent as prepared according to the above was pipetted in amounts of 0.5, 1.0, 1.5 and 2.0 ml respectively into four different 50 ml volumetric flasks and each flask was diluted to the mark with deionized water. The four standards were each well mixed. Each standard contained 0.25, 0.50, 0.75 and 1.00 mg. protein per/ml respectively. Absorbance of each standard was obtained at a wavelength of 280 nm using 10 mm silica cells on a Beckman Model 25 spectrophotometer using deionized water as a blank. A standard graph was prepared by plotting absorbance vs. concentration of each protein standard (mg. Protein/ml) on linear graph paper. The best possible straight line to fit most of the points and the origin was drawn.
Procedure
To at least three significant figures two and four grams of the Al 2 O 3 samples were weighed into two separate 50 ml glass stoppered centrifuge tubes (concentration of each sample was approximately 40 mg and 80 mg Al 2 O 3 ). A sufficient amount of deionized water was added from a burette so that grams of sample plus milliliters of water equaled 17.0 mls (if the density of the suspension was significantly different from one, corrections were made for the sample volume). The samples were shaken gently to disperse the suspension. 3.00 ml (150 mg of protein) of protein reagent (Bovine Albumin F.V, 5% Solution) solution was then added. The tubes were then mixed gently and placed on a Burrell wrist action shaker. The tubes were shaken gently at a setting of 2 for 15 minutes.
The tubes were centrifuged for 15 minutes at 2000 to 2500 RPM. The supernatant was filtered through a millipore HA (0.45 μm) membrane filter paper. 10 ml of clear filtrate was pipetted into a 100 ml volumetric flask and diluted to volume with deionized water. The absorbance for each sample at 280 nm wavelength was read using 10 mm silica cells, the model 25 spectrophotometer and deionized water as a blank. The concentration of each non-adsorbed protein sample was obtained in mg/ml at approximately 40 mg Al 2 O 3 and 80.0 mg Al 2 O 3 level from the standard graph.
Calculations
@approximately 40 mg Al 2 O 3 level, ##EQU2## And,
approximately 80 mg Al 2 O 3 level, ##EQU3##
Results
The average of both the mg Protein/mg Al 2 O 3 were taken at approximately 40 mg Al 2 O 3 and 80 mg Al 2 O 3 level and reported as mg Protein/mg Al 2 O 3 .
Using the above procedure, protein-binding capacities were determined for various co-dried compounds in Examples 51-71 and the results are given in Table XIII herein.
Since surface area plays a major role in the adsorption measured in this test, micronization might increase the values of the co-dried systems and not the Al 2 O 3 dried without additives.
Examples 72-91
Protein Binding
The same test procedure as in Examples 51-71 was utilized in Examples 72-91 except the pH was adjusted to 5.5. The glycerine control (100% glycerine) test was not applicable, since both it and the protein solution were soluble in mixed form.
A plot of protein binding capacity vs. % glycerine for co-dried Al 2 O 3 -glycerine without acid is given in the FIGURE (Example Nos. 72-75). The results for Examples 72-91 are given in Table XIV herein.
Examples 92-100
In Examples 92-100, co-dried systems of Al 2 O 3 -glycerine prepared in accordance with this invention were evaluated with and without the addition of acid (HCl). The results for Examples 92-100 are given in Table XV herein. It is evident from Table XV that resuspendability was afforded to only those systems employing acid. The use of acid also increased the protein binding capacity of the co-dried systems.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention.

TABLE I______________________________________Example No. % Al.sub.2 O.sub.3 Al.sub.2 O.sub.3 /Glycerol Ratio in______________________________________ Slurry1 61.4 6/12 60.1 3/13 58.6 2/14 57.9 3/25 64.47 3/0______________________________________


TABLE II______________________________________Example pH Al.sub.2 O.sub.3 /GlycerolNo. Measured Ratio In Slurry *Description______________________________________1A 4.7 6/1 fluid gel1B 6.0 6/1 thick fluid gel2A 5.1 3/1 gel2B 6.3 3/1 gel3A 4.7 2/1 fluid gel3B 6.3 2/1 gel4A 4.0 3/2 fluid gel4B 6.3 3/2 gel5A 4.7 3/1 fluid gel5B 6.2 3/0 with 0.2 cm unsuspended powder______________________________________ *All resuspensions described at a minimum of 1 day, maximum of 30 days.


TABLE III______________________________________Example Al.sub.2 O.sub.3 /Glycerol RatioNo. % Al.sub.2 O.sub.3 % Glycerol Slurry Powder______________________________________6 62.18 10.5 6/1 5.9/17 59.20 16.5 3/1 3.6/18 56.70 19.7 2/1 2.9/19 55.77 22.9 3/2 4.9/210 64.47 -- 3/0 3/0______________________________________


TABLE IV______________________________________Example MeasuredNo. pH Description______________________________________6 5.8 gel7 5.8 gel8 5.6 gel9 5.7 gel10 5.9 0.5 cm unsuspended powder in 6 cm supernatant______________________________________


TABLE V______________________________________Example Measured Al.sub.2 O.sub.3 /GlycerolNo. pH in Slurry Description______________________________________11 5.5 3/1 gel12 5.9 3/1 gel13 6.4 3/1 fluid gel14 7.2 3/1 0.5 cm unsus- pended powder and 6 cm super- natant15 7.9 3/1 same as Example 14______________________________________


TABLE VI______________________________________Example Measured Approx. % Al.sub.2 O.sub.3No. PH Concentration in Vial Description______________________________________16 5.7 2 fluid gel17 5.7 4 gel18 5.7 6 gel19 5.8 8 very thick gel20 5.7 10 very thick gel______________________________________


TABLE VII__________________________________________________________________________ ##STR1##__________________________________________________________________________


TABLE VIII______________________________________Example Measured %No. pH Al.sub.2 O.sub.3 Resuspension Description______________________________________21A 4.6 4 fair 0.5 cm settled powder below hazy liquid21B 5.0 8 fair 2 cm clear liquid above unsuspend- ed powder22A 5.5 4 fair 1 cm settled pow- der above hazy liquid22B 6.2 8 fair 2 cm clear liquid above unsuspend- ed powder23A 4.2 4 fair 0.5 cm settled powder below hazy powder23B 5.7 8 good thick suspension24A 5.2 4 fair 1.5 cm settled powder below hazy liquid24B 6.2 8 fair 1.5 cm clear liquid above settled powder25A 8.4 4 no unsuspended powder25B 8.5 8 no unsuspended powder26A 8.5 4 no unsuspended powder26B 8.4 8 no unsuspended powder27A 5.2 4 good gel27B 6.5 8 good very thick gel28A 4.1 4 good fluid gel28B 6.2 8 good very thick qel29A 8.9 4 no unsuspended powder29B 8.9 8 no unsuspended powder30A 6.3 4 no unsuspended powder30B 6.5 8 no unsuspended powder31A 5.6 4 good gel31B 5.8 8 good very thick gel32A 6.3 4 no unsuspended powder32B 6.5 8 no unsuspended powder33A 6.3 4 no unsuspended powder33B 6.5 8 no unsuspended powder______________________________________ *All descriptions made at minimum 1 day, maximum 30 days.


TABLE IX______________________________________Reevaluation Of Resuspendability TakenAbout Six Weeks Later Than Those Taken In Table VIIIExample No. % Al.sub.2 O.sub.3 Resuspension *Description______________________________________21A 4 good gel21B 8 good gel22A 4 fair 1.5 cm clear liquid above 4 cm resus- pended powder22B 8 fair 0.5 cm clear liquid above 5 cm resus- pended powder23A 4 good gel23B 8 good gel24A 4 good fluid gel24B 8 fair 1 cm clear liquid above 4.5 cm resus- pended powder25A 4 no unsuspended powder25B 8 no unsuspended powder26A 4 no unsuspended powder26B 8 no unsuspended powder27A 4 good gel27B 8 good very thick gel28A 4 good gel28B 8 good very thick gel29A 4 no unsuspended powder29B 8 no unsuspended30A 4 fair 1 cm clear liquid above 4.5 cm resus- pended powder30B 8 fair 1.5 cm clear liquid above 4 cm resus- pended powder31A 4 good gel31B 8 good very thick gel32A 4 no unsuspended powder32B 8 no unsuspended powder______________________________________ *All descriptions made at minimum 1 day, maximum 30 days.


TABLE X______________________________________Additive % Al.sub.2 O.sub.3______________________________________none 65.31sucrose 56.07lactose 56.36sorbitol 56.74propylene glycol 63.74urea 59.29Carbowax 600 56.83Carbowax 400 56.42Veegum 54.40corn starch 51.26PVP K-30 55.35citric acid 57.66stearic acid 63.66gelatin 57.75PVP K-60 55.68Carbowax 200 54.21glycine 58.61L-glutamic acid 58.72beta-alanine 58.46potassium citrate 56.97______________________________________


TABLE XI______________________________________Example Wt. % Al.sub.2 O.sub.3 Drops HClNo. Additive Resuspension (31%) Added______________________________________34B sucrose 8 3 (0.14 g)34C sucrose 4 334D sucrose 8 5 (0.24 g)35A lactose 4 335B lactose 8 535C lactose 4 335D lactose 8 336A sorbitol 4 336B sorbitol 8 536C sorbitol 4 336D sorbitol 8 337A propylene glycol 4 337B propylene glycol 8 537C propylene glycol 4 337D propylene glycol 8 338A Carbowax 200 4 338B Carbowax 200 8 338C Carbowax 200 4 338D Carbowax 200 8 539A Carbowax 400 4 339B Carbowax 400 8 539C Carbowax 400 4 339D Carbowax 400 8 340A Carbowax 600 4 340B Carbowax 600 8 540C Carbowax 600 4 340D Carbowax 600 8 341A stearic acid 4 341B stearic acid 8 541C stearic acid 4 341D stearic acid 8 342A citric acid 4 542B citric acid 8 342C citric acid 4 342D citric acid 8 343A potassium 4 3 citrate43B potassium 8 5 citrate43C potassium 8 3 citrate44A corn starch 4 344B corn starch 8 544C corn starch 4 344D corn starch 8 345A urea 4 545B urea 8 345C urea 4 345D urea 8 346A glycine 4 346B glycine 8 546C glycine 4 346D glycine 8 347A beta-alanine 4 347B beta-alanine 8 547C beta-alanine 4 347D beta-alanine 8 348A L-glutamic 4 3 acid48B L-glutamic 8 5 acid48C L-glutamic 4 0 acid48D L-glutamic 8 3 acid49A gelatin 4 349B gelatin 8 549C gelatin 8 350A Veegum 4 350B Veegum 8 550C Veegum 4 350D Veegum 8 3______________________________________


TABLE XII__________________________________________________________________________Example AdjustedNo. Additive pH % Al.sub.2 O.sub.3 Resuspension *Description__________________________________________________________________________34A sucrose 5.2 4 good thick gel34B sucrose 6.7 8 good fluid gel34C sucrose 6.0 4 good thick gel34D sucrose 5.6 8 good very thick gel35A lactose 5.5 4 good thick gel35B lactose 5.6 8 good thick gel35C lactose 6.3 4 good thick fluid gel35D lactose 6.6 8 good fluid gel36A sorbitol 5.5 4 good gel36B sorbitol 6.4 8 good very thick gel36C sorbitol 6.3 4 good fluid gel36D sorbitol 6.5 8 good gel37A propylene 5.2 4 good gelglycol37B propylene 6.5 8 fair 0.5 cm clearglycol liquid on 5 cm powder37C propylene 6.5 4 no unsuspendedglycol powder37D propylene 6.7 8 fair 0.5 cm clearglycol liquid on 5 cm powder38A Carbowax 200 5.5 4 good thick fluid gel38B Carbowax 200 6.4 8 good thick fluid gel38C Carbowax 200 5.8 4 good gel38D Carbowax 200 5.6 8 good gel39A Carbowax 400 4.6 4 good thick fluid gel39B Carbowax 400 6.1 8 good very thick gel39C Carbowax 400 6.0 4 good gel39D Carbowax 400 6.4 8 good thick fluid gel40A Carbowax 600 4.7 4 good thick fluid gel40B Carbowax 600 5.1 8 good gel40C Carbowax 600 5.4 4 good thick fluid gel40D Carbowax 600 6.2 8 no unsuspended powder41A stearic acid 4.1 4 no unsuspended powder with hazy liquid41B stearic acid 5.1 8 no same as above41C stearic acid 4.3 4 no same as above41D stearic acid 5.2 8 no same as above42A citric acid 2.5 4 no unsuspended powder42B citric acid 2.5 8 no same as above42C citric acid 2.6 4 no same as above42D citric acid 2.7 8 no same as above43A potassium 5.8 4 no same as abovecitrate43B potassium 6.6 8 no same as abovecitrate43C potassium 8.3 8 no same as abovecitrate44A corn starch 4.8 4 good fluid gel44B corn starch 5.1 8 good thick fluid gel44C corn starch 6.1 4 no unsuspended powder44D corn starch 6.2 8 no same as above45A urea 4.9 4 good fluid gel45B urea 5.7 8 good very thick gel45C urea 5.6 4 good thick gel45D urea 6.5 8 no unsuspended powder46A glycine 5.2 4 good gel46B glycine 5.4 8 good gel46C glycine 5.6 4 good gel46D glycine 6.6 8 fair 1 cm clear liquid above 4.5 cm powder47A beta-alanine 5.0 4 good fluid gel47B beta-alanine 6.0 8 good gel47C beta-alanine 6.2 4 good gel47D beta-alanine 6.7 8 fair 0.5 cm clear liquid above powder48A L-glutamic 3.7 4 good gelacid48B L-glutamic 3.9 8 good thick fluidacid gel48C L-glutamic 4.9 4 no unsuspended powder48D L-glutamic 4.1 8 good thick fluid gel49A gelatin 5.3 4 no same as above49B gelatin 6.1 8 no same as above49C gelatin 6.6 8 no same as above50A Veegum 5.5 4 no same as above50B Veegum 6.3 8 no same as above50C Veegum 6.6 4 no same as above50D Veegum 6.7 8 no same as above__________________________________________________________________________


TABLE XIII______________________________________Protein Binding Capacity of Al.sub.2 O.sub.3 with Additives* mg. of ProteinExample adsorbedNo. Sample Description % Al.sub.2 O.sub.3 mg. of Al.sub.2 O.sub.3______________________________________51 Al.sub.2 O.sub.3 slurry (no additive) 3.37 1.3452 Al.sub.2 O.sub.3 w/L-glutamic acid 58.72 0.4853 Al.sub.2 O.sub.3 w/Carbowax-600 56.83 0.2554 Al.sub.2 O.sub.3 w/beta-alanine 58.46 0.2455 Al.sub.2 O.sub.3 w/Carbowax-400 56.42 0.2156 Al.sub.2 O.sub.3 w/stearic acid 63.62 0.2057 Al.sub.2 O.sub.3 w/K-citrate 56.92 0.2058 Al.sub.2 O.sub.3 w/citric acid 57.66 0.1759 Al.sub.2 O.sub.3 w/Glycine 58.61 0.1760 Al.sub.2 O.sub.3 w/propylene glycol 63.74 0.1461 Al.sub.2 O.sub.3 w/urea 59.29 0.1362 Al.sub.2 O.sub.3 w/sucrose 56.07 0.1263 Al.sub.2 O.sub.3 w/Carbowax-200 59.21 0.1264 Al.sub.2 O.sub.3 (No additive) 65.31 0.1165 Al.sub.2 O.sub.3 w/sorbitol 56.74 0.1166 Al.sub.2 O.sub.3 w/gelatin 57.75 0.1067 Al.sub.2 O.sub.3 w/PVP (K-60) 55.68 0.0968 Al.sub.2 O.sub.3 w/PVP (K-30) 55.35 0.0869 Al.sub.2 O.sub.3 w/lactose 56.36 0.0470 Al.sub.2 O.sub.3 w/Veegum 54.40 0.071 Al.sub.2 O.sub.3 w/corn starch 51.26 0.0______________________________________ *Al.sub.2 O.sub.3 powder with 3:1 additive ratio


TABLE XIV__________________________________________________________________________ Protein Binding PB @ PB @* Nat'l pH pH 5.51ExampleCo-Dried % % Approx. Actual Nat'l mg ProteinNo. Additive Al.sub.2 O.sub.3 Additive Al.sub.2 O.sub.3 Al.sub.2 O.sub.3 pH mg Al.sub.2 O.sub.3__________________________________________________________________________72 None 65.3 0 -- -- 8.6 0.11 073 Glycerine 61.4 10.75 6/1 5.7/1 0.09 0.5474 Glycerine 60.1 21.5 3/1 2.8/1 8.5 0.11 0.9575 Glycerine 57.9 43 1.5/1 1.3/1 0.26 1.2576 Glycerine/ 3/1 5.5 1.7 1.7HCl77 Glycerine/ 62.1 15.7 4.0/1 4.7 1.7HCl78 None 65.3 0 -- -- 8.6 0.11 079 Glycerine 60.1 21.6 3/1 2.8/1 8.5 0.11 0.9580 Carbowax 56.4 3/1 8.1 0.21 0.7340081 Lactose 56.4 3/1 8.8, 0.04 0.67 8.782 Glycine 58.6 3/1 8.1 0.17 0.5883 Sorbitol 56.7 3/1 8.8, 0.11 0.36 8.784 Propylene 63.7 3/1 8.7, 0.14 0.34glycol 8.685 Citric Acid 57.7 3/1 3.4 0.17 0.0186 Stearic Acid 63.6 3/1 7.8 0.20 0.0587 Corn Starch 51.3 3/1 8.2 0 088 Gelatin 57.8 3/1 8.0 0.10 089 K Citrate 57.0 3/1 9.4 0.20 0.1.90 Arlacel 58.0 3/1 8.2 0165**91 Arlacel 55.9 3/1 0.17165**__________________________________________________________________________ *Adjusted with HCl or caustic to yield pH 5.51 **Arlacel 165 95% glycerol monostearate and 5% polyethylene glycol monostearate


TABLE XV__________________________________________________________________________Examples 92-100Co-Dried Al.sub.2 O.sub.3 and Glycerol - With and Without HCl Protein Binding pH ofExample Al.sub.2 O.sub.3 /Glycerol % Al.sub.2 O.sub.3 in mg Protein/ 4% Al.sub.2 O.sub.3No. HCl Ratio in Slurry Powder mg Al.sub.2 O.sub.3 Suspension Resuspendability__________________________________________________________________________92 No HCl 3/1 58.9 0.04 9.0 Poor93 No HCl 3/0.5 61.4 0.09 8.5 Poor94 No HCl 3/1 60.1 0.11 8.5 Poor95 No HCl 3/1.5 58.6 0.15 8.5 Poor96 No HCl 3/2 57.9 0.26 8.5 Poor97 No HCl 3/1 62.48 0.4 8.5 Poor98 HCl 3/1 62.48 1.7 4.7* Good99 HCl 3/1 -- 1.6 * Good100 HCl 3/1 58.13 1.78 6.2 Good__________________________________________________________________________ *pH was adjusted to 5.5 before protein binding test